This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
Proliferating Cell Nuclear Antigen (PCNA, SEQ ID NO: 1) is a nuclear homotrimeric protein that encircles chromatin-bound DNA with attributes of a processivity factor in DNA damage repair and replication (Kelman, Z., et al. Nucleic Acids Res. 1995, 23 (18), 3613-3620; Pedley, A. M., et al. PLoS ONE 2014, 9 (7), e102481). It mediates protein complex formation in base excision, mismatch, nucleotide excision and translation synthesis DNA repair pathways (.Maga, G., et al. J. Cell Sci. 2003, 116 (15), 3051-3060; Moldovan, G.-L., et al. Cell 2007, 129 (4), 665-679); Stoimenov, I., et al. Biochem. Soc. Trans. 2009, 37 (Pt 3), 605-613). PCNA also acts as a regulator of cell cycle progression, chromatin remodeling and transcription. More than 200 proteins are currently proposed to interact with PCNA implicating involvement in all facets of the DNA damage response (DDR) (Chatr-Aryamontri, A., et al. Nucleic Acids Res. 2015, 43 (Database issue), D470-D478). Many of these proteins share a binding site on PCNA called the PCNA-Interacting Protein (PIP) box domain (Hishiki, A., et al. J. Biol. Chem. 2009, 284 (16), 10552-10560; Gulbis, J. M., et al. Cell 1996, 87 (2), 297-306; Bruning, J. B., et al., Struct. Lond. Engl. 1993 2004, 12 (12), 2209-2219). Antagonism of PCNA association with PIP box-containing proteins could ultimately impair the cell's ability to repair or replicate DNA. As evidence of this approach, the deletion of the PIP box within c-Abl disrupts increases the nuclear c-Abl apoptotic function in DNA-damaged cells (He, X., et al. Apoptosis Int. J. Program. Cell Death 2009, 14 (3), 268-275). While various strategies currently exist for targeting DNA repair pathways, functional antagonists of PCNA could serve uniquely to inhibit the DNA damage tolerance pathway, post-replication repair, specifically disrupting RAD6-dependent translesion synthesis as well as the “template switch” pathway (Lehmann, A. R., et al., DNA Repair 2006, 5 (12), 1495-1498; Hoege, C., et al. Nature 2002, 419 (6903), 135-141). The discovery of such an inhibitor would have potential as a sensitizing or synergistic agent in the development of new combination therapies.